pyridine, diluted with CH2C12 (20 ml), and cooled to -60°in a Dry Ice-acetone bath. While stirring at -60°a mixture of 12.5% phosgene in benzene (9.1 ml, 0.010 mol) and CH2C12 (25 ml) was added dropwise over 16 min. After slow equilibration to 25°the reaction mixture was evaporated to dryness under vacuum and the residue was broken up with water, filtered, and dried to give 3.48 g of crude 13. Re crystallization from EtOH gave 3.24 g (85%) of pure 13 as colorless, thin, lathe-like crystals: mp 145-146°; ir (CHCls) 5.69 µ (C=0); nmr (CDC1,) 1.32,

[3-(1,4-Cyclohexadienyl)-L-alanine,8-lysine]vasopressin, otherwise known as [3-(2,5-dihydrophenylalanine),8-lysine]vasopressin or [DiHPhe3]lysine-vasopressin, has been synthesized in an attempt to utilize 2,5-dihydrophenylalanine (DiHPhe) to evaluate the contribution of aromaticity in position 3 to biological activity. The analogue has the same primary structure as lysine-vasopressin, except that two additional hydrogen atoms are present on the ring moiety of the phenylalanine residue in position 3. The key intermediate was the protected nonapeptide N-carbobenzoxy-S-benzyl-L-cysteinyl-L-tyrosyldihydrophenyl-L-alanyl-L-glutaminyl-L-asparaginyl-S-benzyl-L-cysteinyl-L-prolyl-N epsilon-tosyl-L-lysylglycinamide that was synthesized stepwise by the solid-phase technique. Deprotection with sodium in liquid ammonia was followed by sulfhydryl oxidation with I2 to give the hormone analogue. [DiHPhe3]lysine-vasopressin exhibited 125--130 units/mg of antidiuretic, 129--132 units/mg of rat pressor, and 6 units/mg of rat uterus contracting activity. To confirm the presence of DiHPhe in the analogue, an enzymatic procedure employing Aspergillus oryzae was developed that liberates in high yield the amino acid residue in position 3 of the posterior pituitary hormone structure. This study should be applicable to other biologically active peptides.

Derivate von L‐1,4‐Cyclohexadien‐1‐alanin‐methylester‐hydrochlorid (Ia) werden in der angegebenen Weise hergestellt.

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